The discussion that follows is provided as background to aid the reader in understanding the present invention and is not intended, nor is it to be construed, as being prior art to the invention.
A gel is a three-dimensional polymeric network that has absorbed a liquid to form a stable, usually soft and pliable, composition having a non-zero shear modulus. When the liquid absorbed by a gel is water, the gel is called a hydrogel. Water may comprise a significant weight percent of a hydrogel. This, plus the fact that many hydrogel-forming polymers are biologically inert, makes hydrogels particularly useful in a wide variety of biomedical applications.
For example, hydrogels are widely used in soft contact lens. They are also used as burn and wound dressings, with and without incorporated drugs that can be released from the gel matrix to aid in the healing process (e.g., see U.S. Pat. Nos. 3,063,685 and 4,272,518). Hydrogels have been used as coatings to improve the wettability of the surfaces of medical devices such as blood filters (U.S. Pat. No. 5,582,794). They have also found utility as devices for the sustained release of biologically active substances. For example, U.S. Pat. No. 5,292,515 discloses a method of preparing a hydrophilic reservoir drug delivery device. The '515 patent discloses that drug release rates can be controlled by changing the water content of the hydrogel subcutaneous implant, which directly affects its permeability coefficient.
In all the above applications, the gel or hydrogel is in bulk form, that is, it is an amorphous mass of material with no discernable regular internal structure. Bulk hydrogels have slow swelling rates due to the large internal volume relative to the surface area through which water must be absorbed. Furthermore, a substance dissolved or suspended in the absorbed water will diffuse out of the gel at a rate that depends on the distance it must travel to reach the surface of the gel. That is, molecules near the surface of the hydrogel will escape quickly, whereas molecules deeper within the matrix will take a much longer time to reach the outer surface of the gel. This situation can be ameliorated to some extent by using particulate gels. If each particle is sufficiently small, substances dispersed in the particles will diffuse to the surface and be released at approximately the same time.
Particulate gels can be formed by a number of procedures such as direct or inverse emulsion polymerization (Landfester, et al., Macromolecules, 2000, 33:2370) or they can be created from bulk gels by drying the gel and then grinding the resulting xerogel to particles of a desired size. The particles can then be re-solvated to form particulate gels. Particles having sizes in the micro (10−6 meters (m)) to nano (10−9 m) diameter range can be produced by this means. Molecules of a substance occluded by particles in these size ranges will all have about the same distance to travel to reach the outer surface of the particle and will exhibit near zero-order release kinetics. However, particulate gels have their problems. For instance, it is difficult to control the dissemination of the particles to, and localization at, a selected target site. Furthermore, while bulk hydrogels can be rendered shape-retentive, making them useful as biomaterials in a variety of medical applications, currently available particulate gels, cannot.
U.S. Pat. No. 7,351,430 , discloses a shape-retentive aggregate formed from hydrogel particles, thus combining the shape-retentiveness of bulk hydrogels with the substance release control of particulate gels. The '430 Patent discloses a method of forming the shape-retentive aggregate comprising preparing a suspension of hydrogel particles in water and concentrating the suspension until the particles coalesce into a shape-retentive aggregate held together by non-covalent bond physical forces including but not limited hydrophobic/hydrophilic interactions and hydrogen bonds.
It would be useful to have a method of forming shape-retentive gel aggregates in situ, such that the shape of the aggregate would be dictated by the shape of the locus of application. This would be particularly useful where the locus application is in vivo, e.g., biomedical applications such as joint reconstruction, wound repair, drug delivery and cosmetic surgery. The present invention provides such a method.